Inhibition of food intake by neuropeptide Y Y5 receptor antisense oligodeoxynucleotides

Schaffhauser, Andrea O.; Stricker–Krongrad, Alain; Brunner, L; Cumin, F.; Gerald, Christophe; Whitebread, Steven; Criscione, Leoluca; Hofbauer, Karl G.

doi:10.2337/diabetes.46.11.1792

Cited by 82 publications

(46 citation statements)

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“…Administration of antisense oligonucleotides to the Y 5 receptor inhibits food intake (Schaffhauser et al 1997), and Y 5 receptor-deficient mice have an attenuated response to NPY (Marsh et al 1998). However, Y 5 receptor density in the hypothalamus appears to be reduced in response to fasting and upregulated in dietary-induced obesity (Widdowson et al 1997).…”

Section: Hypothalamic Neuropeptidesmentioning

confidence: 99%

Appetite control

Wynne¹,

Stanley²,

McGowan³

et al. 2005

Journal of Endocrinology

463

403

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Our understanding of the physiological systems that regulate food intake and body weight has increased immensely over the past decade. Brain centres, including the hypothalamus, brainstem and reward centres, signal via neuropeptides which regulate energy homeostasis. Insulin and hormones synthesized by adipose tissue reflect the long-term nutritional status of the body and are able to influence these circuits. Circulating gut hormones modulate these pathways acutely and result in appetite stimulation or satiety effects. This review discusses central neuronal networks and peripheral signals which contribute energy homeostasis, and how a loss of the homeostatic process may result in obesity. It also considers future therapeutic targets for the treatment of obesity.

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Section: Hypothalamic Neuropeptidesmentioning

confidence: 99%

Appetite control

Wynne¹,

Stanley²,

McGowan³

et al. 2005

Journal of Endocrinology

463

403

View full text Add to dashboard Cite

show abstract

“…The pharmacology of the Y5 receptor matches closely the potency of the orexigenic effects of a range of NPY derivatives (Gerald et al 1996), and it has been shown that reducing Y5 receptor availability, either by using antisense oligodeoxynucleotides targeted against Y5 mRNA (Schaffauser et al 1997) or with a synthetic high-affinity Y5 antagonist (Criscione et al 1998), can decrease spontaneous feeding and the hyperphagia induced by central injection of exogenous NPY. Interestingly, however, the Y5 'knockout' mouse shows no reductions in feeding or weight (Erickson et al 1996a).…”

Section: Neuropeptide Y and Energy Homeostasismentioning

confidence: 99%

The hypothalamus and the regulation of energy homeostasis: lifting the lid on a black box

2000

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The hypothalamus is the focus of many peripheral signals and neural pathways that control energy homeostasis and body weight. Emphasis has moved away from anatomical concepts of ‘feeding’ and ‘satiety’ centres to the specific neurotransmitters that modulate feeding behaviour and energy expenditure. We have chosen three examples to illustrate the physiological roles of hypothalamic neurotransmitters and their potential as targets for the development of new drugs to treat obesity and other nutritional disorders. Neuropeptide Y (NPY) is expressed by neurones of the hypothalamic arcuate nucleus (ARC) that project to important appetite-regulating nuclei, including the paraventricular nucleus (PVN). NPY injected into the PVN is the most potent central appetite stimulant known, and also inhibits thermogenesis; repeated administration rapidly induces obesity. The ARC NPY neurones are stimulated by starvation, probably mediated by falls in circulating leptin and insulin (which both inhibit these neurones), and contribute to the increased hunger in this and other conditions of energy deficit. They therefore act homeostatically to correct negative energy balance. ARC NPY neurones also mediate hyperphagia and obesity in the ob/ob and db/db mice and fa/fa rat, in which leptin inhibition is lost through mutations affecting leptin or its receptor. Antagonists of the Y5 receptor (currently thought to be the NPY ‘feeding’ receptor) have anti-obesity effects. Melanocortin-4 receptors (MC4-R) are expressed in various hypothalamic regions, including the ventromedial nucleus and ARC. Activation of MC4-R by agonists such as α-melanocyte-stimulating hormone (a cleavage product of pro-opiomelanocortin which is expressed in ARC neurones) inhibits feeding and causes weight loss. Conversely, MC4-R antagonists such as ‘agouti’ protein and agouti gene-related peptide (AGRP) stimulate feeding and cause obesity. Ectopic expression of agouti in the hypothalamus leads to obesity in the AVY mouse, while AGRP is co-expressed by NPY neurones in the ARC. Synthetic MC4-R agonists may ultimately find use as anti-obesity drugs in human subjects Orexins-A and -B, derived from prepro-orexin, are expressed in specific neurones of the lateral hypothalamic area (LHA). Orexin-A injected centrally stimulates eating and prepro-orexin mRNA is up regulated by fasting and hypoglycaemia. The LHA is important in receiving sensory signals from the gut and liver, and in sensing glucose, and orexin neurones may be involved in stimulating feeding in response to falls in plasma glucose.

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“…Interestingly, in one of the above studies antisense ODNs directed against the NPY Y 5 receptor did not affect either the microstructure of food intake or the food intake response to galanin, indicating some specificity of this approach. 124 In general, however, concerns about selectivity and toxicity have not been rigorously addressed. Another criticism leveled at the above studies is their failure to determine whether the antisense molecules actually entered their target cells to reduce NPY Y 5 receptor density.…”

Section: Npy Receptor Subtypesmentioning

confidence: 99%

Appetite suppression based on selective inhibition of NPY receptors

Chamorro

Della‐Zuana

et al. 2002

Int J Obes

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AIM:The aim of this review is to critically assess available evidence that blockade of the actions of NPY at one of the five NPY receptor subtypes represents an attractive new drug discovery target for the development of an appetite suppressant drug. RESULTS: Blockade of the central actions of NPY using anti-NPY antibodies, antisense oligodeoxynucleotides against NPY and NPY receptor antagonists results in a decrease in food intake in energy-deprived animals. These results appear to show that endogenous NPY plays a role in the control of appetite. The fact that NPY receptors exist as at least five different subtypes raises the possibility that the actions of endogenous NPY on food intake can be adequately dissociated from other effects of the peptide. Current drug discovery has produced a number of highly selective NPY receptor antagonists which have been used to establish the NPY Y 1 receptor subtype as the most critical in regulating short-term food intake. However, additional studies are now needed to more clearly define the relative contribution of NPY acting through the NPY Y 2 and NPY Y 5 receptors in the complex sequence of physiological and behavioral events that underlie the long-term control of appetite. CONCLUSIONS: Blockade of the NPY receptor may produce appetite-suppressing drugs. However, it is too early to state with certainty whether a single subtype selective drug used alone or a combination of NPY receptor selective antagonists used in combination will be necessary to adequately influence appetite regulation.

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Inhibition of food intake by neuropeptide Y Y5 receptor antisense oligodeoxynucleotides

Cited by 82 publications

References 0 publications

Appetite control

Appetite control

The hypothalamus and the regulation of energy homeostasis: lifting the lid on a black box

Appetite suppression based on selective inhibition of NPY receptors

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